Successful Treatment of Cryptococcal Osteomyelitis and Paraspinous Abscess With Fluconazole and Flucytosine.

ABSTRACT: A patient with thoracic cryptococcal osteomyelitis was treated successfully with the combination of fluconazole and flucytosine. This is the first reported case of cryptococcal osteomyelitis successfully treated with fluconazole and flucytosine.

CRYPTOCOCCUS NEOFORMANS is an encapsulated yeast that usually causes pulmonary infection and meningitis in immunocompromised hosts. It is an uncommon cause of osteomyelitis, with only 41 cases reported in the literature since 1956, the year that amphotericin B became available. [1-3] Treatment of this infection generally involves surgical debridement and amphotericin B with or without flucytosine. In this report, a patient with thoracic osteomyelitis and a paraspinous abscess due to C neoformans was treated with the combination of fluconazole and fluctyosine. This appears to be the first reported case of cryptococcal osteomyelitis successfully treated with fluconazole with or without flucytosine.

CASE REPORT

A 24-year-old woman with a history of sarcoidosis was seen because of a month-long history of back pain. She denied fever, chills, sweats, or weight loss. Neurologic examination was unremarkable. She had not taken corticosteroids for more than a year and was not taking any medications at the time of presentation. Magnetic resonance imaging (MRI) showed destruction of T1 through T3 and a paraspinous fluid collection (Fig 1). Percutaneous fine needle aspiration of the lesion showed budding yeast, and a culture of the fluid grew C neoformans. Lumbar puncture yielded cerebrospinal fluid that was negative for C neoformans by culture, and latex agglutination testing was negative for cryptococcal antigen. Blood cultures were negative, but the serum cryptococcal antigen was positive with a titer of 1:10. Test for human immunodeficiency virus (HIV) was negative. The baseline serum creatinine value was 0.7 mg/dL. Chest radiograph showed hilar adenopathy but no pulmonary infiltrates. The patient was treated with flucon azole, 400 mg per day orally, as an outpatient. Two weeks later, she was admitted to the hospital because of numbness and tingling in the right arm. Repeated MRI showed a larger paraspinous fluid collection as well as spinal cord compression. Surgery was not considered feasible because of the location of the abscess. The patient was placed in a back brace to stabilize the spine. Thirty milliliters of purulent fluid was aspirated percutaneously, and a drain was left in the abscess. A culture of the fluid again grew C neoformans. Fluconazole therapy was discontinued, and treatment with amphoterici B (0.75 mg/kg per day) and flucytosine (150 mg/kg/day) was started. The patient had severe nausea and vomiting, hypomagnesemia (1.1 mg/dL), hypokalemia (3.0 mEq/L), and mild azotemia (serum creatinine value 1.8 mg/dL). She was taking no other medications associated with nephrotoxicity (eg. nonsteroidal anti-inflammatory agents). Amphotericin B therapy was discontinued; the patient had received a cumulative dose of 620 mg. Fluconazole therapy was restarted (400 mg per day orally); flucytosine was decreased to 75 mg/kg/day. Repeated MRI showed resolution of the paraspinous abscess. The percutaneous drain was removed. The patient was discharged home receiving fluconazole, 400 mg/day, and flucytosine, 75 mg/kg/day. The renal insufficiency and hypomagnesemia resolved shortly after amphotericin B was withdrawn, whereas the serum potassium level remained below 3.0 mEq/L for the next 2 months. Follow-up MRI scans showed resolution of the abscess and gibbus formation at T2 (Fig 2). Tests for the serum cryptococcal antigen became negative after 5 months of therapy. The patient was treated for a total of 12 months, the last 11 months with the fluconazole-flucytosine combination. She has had no evidence of relapse 16 months after stopping therapy and no longer wears a back brace.

DISCUSSION

Isolated osteomyelitis due to infection with C neoformans is extremely rare. [1-3] A review of cryptococcal skeletal infections showed that vertebral involvement occurred in 9 of 39 cases (23%). [1] Treatment in these cases usually involved surgical debridement as well as amphotericin B with or without flucytosine. The case presented here is noteworthy in several respects. First, the patient had spinal cord compression, which usually requires surgical debridement and stabilization of the spine. Because of anatomic considerations, ie, the location of the process, surgery was not attempted in this patient. Nevertheless, percutaneous drainage of the paraspinous abscess was crucial to the favorable outcome. Second, the patient was treated with a combination of fluconazole and flucytosine, a regimen that has not previously been reported for the treatment of cryptococcal skeletal infections. Amphotericin B with or without flucytosine has been the standard therapy for severe cryptococcal disease, including osteomye litis. [1,4,5] This combination is fraught with side effects. Amphotericin B-associated nephrotoxicity is common (as occurred in this patient) and potentiates the bone marrow and gastrointestinal toxicities of flucytosine. Amphotericin B monotherapy avoids the flucytosine-associated toxicities but is still complicated by nephrotoxicity, cytopenia, hypokalemia, hypomagnesemia, and infusion-related phlebitis and rigors. Fluconazole has clear advantages over amphotericin B; it is less toxic and can be given orally, obviating the need for a long-term intravenous line. Fluconazole has been shown to be as efficacious as amphotericin B in the treatment of patients with both HIV infection and cryptococcal meningitis, [6] but no literature documents its efficacy for treatment of osteomyelitis. This patient was initially treated with fluconazole alone but had progression of the disease process while receiving monotherapy. Flucytosine has activity against Candida species as well as C neoformans, but it should not be use d as monotherapy because of rapid development of resistance to the compound. It has been used in combination with amphotericin B, and more recently, with fluconazole, for treatment of cryptococcal disease in patients with HIV infection. [5,7] Larsen et al [7] showed that the combination of fluconazole and flucytosine was associated with a higher response rate in the treatment of patients with acquired immunodeficiency syndrome who had cryptococcal meningitis when compared with historical controls treated with either amphotericin B or fluconazole. Side effects severe enough to warrant discontinuing flucytosine therapy were seen in 28% of the patients in this trial, which used flucytosine at a dosage of 150 mg/kg/day. [7] Studies done in mice have shown that the combination of flucytosine and fluconazole is superior to treatment with either drug alone. [8] In vitro data have shown synergistic activity of fluconazole and flucytosine against C neoformans, prompting the suggestion that further combination studies be done using a lower concentration of flucytosine, presumably to reduce side effects of the drug. [9]

Nausea and vomiting, which developed in the patient described here, are common side effects of flucytosine. The dose of the medication was reduced to 75 mg/kg/day to avoid the gastrointestinal side effects. Serum levels of flucytosine were not measured because the dose was reduced to manage gastrointestinal side effects. Because of the reported synergism of the two drugs against C neoformans, it seems likely that the levels would have been adequate to inhibit growth of the organism.

Recent guidelines from the Infectious Disease Society of America (IDSA) recommend treatment with fluconazole for 6 to 12 months for "mild to moderate" cryptococcal disease not involving the central nervous system (ie, non-CNS disease) in immunocompetent patients. [10] The IDSA guidelines suggest that fluconazole in combination with flucytosine is an acceptable regimen for CNS disease in patients with HIV. [10] In the patient under discussion, follow-up MRI and serial serum cryptococcal antigen testing were used to assess response to and duration of antifungal therapy.

In summary, this is the first report of successful treatment of cryptococcal osteomyelitis with fluconazole alone or in combination with another agent. Fluconazole plus flucytosine may be an alternative to amphotericin B with or without flucytosine for patients with cryptococcal osteomyelitis, particularly in patients who have azotemia or electrolyte abnormalities associated with amphotericin B. Reports of better clinical outcomes with the combination of fluconazole and flucytosine in the treatment of cryptococcal meningitis [5,7] suggest that combination therapy may be more effective than treatment with fluconazole alone. Because of the reported synergistic effect of the two drugs against C neoformans, [9] a reduction in the dose of flucytosine probably contributes to better tolerability without a loss in clinical efficacy.

From the Department of Medicine, Brody School of Medicine at East Carolina University, Greenville, NC.

References

(1.) Behrman RE, Masci JR, Nicholas P: Cryptococcal skeletal infections: case report and review. Rev Infect Dis 1990; 12: 181-190

(2.) Chleboun J, Nade S: Skeletal cryptococcosis. J Bone Joint Surg Am 1977; 59:509-514

(3.) Liu PY-F: Cryptococcal osteomyelitis: case report and review. Diagn Microbial Infect Dis 1998; 30:33-35

(4.) Utz JP, Garriques IL, Sande MA, et al: Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J Infect Dis 1975; 132:368-373

(5.) Mayanja-Kizza H, Oishi K, Mitarai S, et al: Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998; 26:1362-1368

(6.) Saag MS, Powderly WG, Cloud GA, et al: Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992; 326:83-89

(7.) Larsen RA, Bozzette SA, Jones BE, et al: Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19:741-745

(8.) Allendoerfer R, Marquis AJ, Rinaldi MG, et al: Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis. Antimicrob Agents Chemother 1991; 35:726-729

(9.) Nguyen MH, Barchiesi F, McGough DA, et al: In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans. Antimicrob Agents Chemother 1995; 39:1691-1695

(10.) Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30:710-718

KEY POINTS

* Isolated osteomyelitis due to infection with C neoformans is extremely rare.

* Treatment in these cases usually involves surgical debridement, as well as amphotericin B with or without flucytosine.

* Nausea and vomiting are common side effects of flucytosine.

* Recent guidelines from the Infectious Disease Society of America recommend treatment with fluconazole for 6 to 12 months for mild to moderate cryptococcal disease not involving the central nervous system.

* Fluconazole plus flucytosine may be an alternative to amphotericin B with or without flucytosine for patients with cryptococcal osteomyelitis.